Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Paul Bastard, Lindsey B Rosen, Qian Zhang, Eleftherios Michailidis, Hans-Heinrich Hoffmann, Yu Zhang, Karim Dorgham, Quentin Philippot, Jérémie Rosain, Vivien Béziat, Jérémy Manry, Elana Shaw, Liis Haljasmägi, Pärt Peterson, Lazaro Lorenzo, Lucy Bizien, Sophie Trouillet-Assant, Kerry Dobbs, Adriana Almeida de Jesus, Alexandre Belot, Anne Kallaste, Emilie Catherinot, Yacine Tandjaoui-Lambiotte, Jeremie Le Pen, Gaspard Kerner, Benedetta Bigio, Yoann Seeleuthner, Rui Yang, Alexandre Bolze, András N Spaan, Ottavia M Delmonte, Michael S Abers, Alessandro Aiuti, Giorgio Casari, Vito Lampasona, Lorenzo Piemonti, Fabio Ciceri, Kaya Bilguvar, Richard P Lifton, Marc Vasse, David M Smadja, Mélanie Migaud, Jérome Hadjadj, Benjamin Terrier, Darragh Duffy, Lluis Quintana-Murci, Diederik van de Beek, Lucie Roussel, Donald C Vinh, Stuart G Tangye, Filomeen Haerynck, David Dalmau, Javier Martinez-Picado, Petter Brodin, Michel C Nussenzweig, Stéphanie Boisson-Dupuis, Carlos Rodríguez-Gallego, Guillaume Vogt, Trine H Mogensen, Andrew J Oler, Jingwen Gu, Peter D Burbelo, Jeffrey I Cohen, Andrea Biondi, Laura Rachele Bettini, Mariella D'Angio, Paolo Bonfanti, Patrick Rossignol, Julien Mayaux, Frédéric Rieux-Laucat, Eystein S Husebye, Francesca Fusco, Matilde Valeria Ursini, Luisa Imberti, Alessandra Sottini, Simone Paghera, Eugenia Quiros-Roldan, Camillo Rossi, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, Gian Luigi Marseglia, Xavier Duval, Jade Ghosn, HGID Lab, NIAID-USUHS Immune Response to COVID Group, COVID Clinicians, COVID-STORM Clinicians, Imagine COVID Group, French COVID Cohort Study Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, John S Tsang, Raphaela Goldbach-Mansky, Kai Kisand, Michail S Lionakis, Anne Puel, Shen-Ying Zhang, Steven M Holland, Guy Gorochov, Emmanuelle Jouanguy, Charles M Rice, Aurélie Cobat, Luigi D Notarangelo, Laurent Abel, Helen C Su, Jean-Laurent Casanova
Abstract
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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References
- Casanova J.-L., Abel L., The human genetic determinism of life-threatening infectious diseases: Genetic heterogeneity and physiological homogeneity? Hum. Genet. 139, 681–694 (2020). 10.1007/s00439-020-02184-w
- Döffinger R., Helbert M. R., Barcenas-Morales G., Yang K., Dupuis S., Ceron-Gutierrez L., Espitia-Pinzon C., Barnes N., Bothamley G., Casanova J.-L., Longhurst H. J., Kumararatne D. S., Autoantibodies to interferon-γ in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin. Infect. Dis. 38, e10–e14 (2004). 10.1086/380453
- Höflich C., Sabat R., Rosseau S., Temmesfeld B., Slevogt H., Döcke W.-D., Grütz G., Meisel C., Halle E., Göbel U. B., Volk H.-D., Suttorp N., Naturally occurring anti–IFN-γ autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans. Blood 103, 673–675 (2004). 10.1182/blood-2003-04-1065
- Kampmann B., Hemingway C., Stephens A., Davidson R., Goodsall A., Anderson S., Nicol M., Schölvinck E., Relman D., Waddell S., Langford P., Sheehan B., Semple L., Wilkinson K. A., Wilkinson R. J., Ress S., Hibberd M., Levin M., Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-γ. J. Clin. Invest. 115, 2480–2488 (2005). 10.1172/JCI19316
- Puel A., Picard C., Lorrot M., Pons C., Chrabieh M., Lorenzo L., Mamani-Matsuda M., Jouanguy E., Gendrel D., Casanova J.-L., Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008). 10.4049/jimmunol.180.1.647
- Puel A., Döffinger R., Natividad A., Chrabieh M., Barcenas-Morales G., Picard C., Cobat A., Ouachée-Chardin M., Toulon A., Bustamante J., Al-Muhsen S., Al-Owain M., Arkwright P. D., Costigan C., McConnell V., Cant A. J., Abinun M., Polak M., Bougnères P.-F., Kumararatne D., Marodi L., Nahum A., Roifman C., Blanche S., Fischer A., Bodemer C., Abel L., Lilic D., Casanova J.-L., Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010). 10.1084/jem.20091983
- Kisand K., Bøe Wolff A. S., Podkrajsek K. T., Tserel L., Link M., Kisand K. V., Ersvaer E., Perheentupa J., Erichsen M. M., Bratanic N., Meloni A., Cetani F., Perniola R., Ergun-Longmire B., Maclaren N., Krohn K. J. E., Pura M., Schalke B., Ströbel P., Leite M. I., Battelino T., Husebye E. S., Peterson P., Willcox N., Meager A., Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010). 10.1084/jem.20091669
- Ku C.-L., Chi C.-Y., von Bernuth H., Doffinger R., Autoantibodies against cytokines: Phenocopies of primary immunodeficiencies? Hum. Genet. 139, 783–794 (2020). 10.1007/s00439-020-02180-0
- Isaacs A., Lindenmann J., Virus interference. I. The interferon. Proc. R. Soc. Lond. B 147, 258–267 (1957). 10.1098/rspb.1957.0048
- Isaacs A., Lindenmann J., Valentine R. C., Virus interference. II. Some properties of interferon. Proc. R. Soc. Lond. B 147, 268–273 (1957). 10.1098/rspb.1957.0049
- Gresser I., Wherefore interferon? J. Leukoc. Biol. 61, 567–574 (1997). 10.1002/jlb.61.5.567
- Hoffmann H.-H., Schneider W. M., Rice C. M., Interferons and viruses: An evolutionary arms race of molecular interactions. Trends Immunol. 36, 124–138 (2015). 10.1016/j.it.2015.01.004
- de Weerd N. A., Vivian J. P., Lim S. S., Huang S. U.-S., Hertzog P. J., Structural integrity with functional plasticity: What type I IFN receptor polymorphisms reveal. J. Leukoc. Biol. 108, 909–924 (2020). 10.1002/JLB.2MR0420-152R
- Darnell J. E. Jr., ., STATs and gene regulation. Science 277, 1630–1635 (1997). 10.1126/science.277.5332.1630
- Vallbracht A., Treuner J., Flehmig B., Joester K. E., Niethammer D., Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289, 496–497 (1981). 10.1038/289496a0
- Meager A., Visvalingam K., Peterson P., Möll K., Murumägi A., Krohn K., Eskelin P., Perheentupa J., Husebye E., Kadota Y., Willcox N., Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLOS Med. 3, e289 (2006). 10.1371/journal.pmed.0030289
- Panem S., Check I. J., Henriksen D., Vilcek J., Antibodies to alpha-interferon in a patient with systemic lupus erythematosus. J. Immunol. 129, 1–3 (1982).
- Zhang Q., Bastard P., Liu Z., Le Pen J., Moncada-Velez M., Chen J., Ogishi M., Sabli I. K. D., Hodeib S., Korol C., Rosain J., Bilguvar K., Ye J., Bolze A., Bigio B., Yang R., Augusto Arias Sierra A., Zhou Q., Zhang Y., Onodi F., Korniotis S., Karpf L., Philippot Q., Chbihi M., Bonnet-Madin L., Dorgham K., Smith N., Schneider W. M., Razooky B. S., H.-H. Hoffmann, Michailidis E., Moens L., Han J. E., Lorenzo L., Bizien L., Meade P., Neehus A.-L., Ugurbil A. C., Corneau A., Kerner G., Zhang P., Rapaport F., Seeleuthner Y., Manry J., Masson C., Schmitt Y., Schlüter A., Le Voyer T., Khan T., Li J., Fellay J., Roussel L., Shahrooei M., Alosaimi M. F., Mansouri D., Al-Saud H., Al-Mulla F., Almourfi F., Al-Muhsen S. Z., Alsohime F., Al Turki S., Hasanato R., van de Beek D., Biondi A., Bettini L. R., D’Angio M., Bonfanti P., Imberti L., Sottini A., Paghera S., Quiros-Roldan E., Rossi C., Oler A. J., Tompkins M. F., Alba C., Vandernoot I., Goffard J.-C., Smits G., Migeotte I., Haerynck F., Soler-Palacin P., Martin-Nalda A., Colobran R., Morange P.-E., Keles S., Çölkesen F., Ozcelik T., Yasar K. K., Senoglu S., Karabela Ş. N., Rodríguez-Gallego C., Novelli G., Hraiech S., Tandjaoui-Lambiotte Y., Duval X., Laouenan C., COVID-STORM Clinicians, COVID Clinicians, Imagine COVID group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, NIAID-USUHS/TAGC COVID Immunity Group, Snow A. L., Dalgard C. L., Milner J., Vinh D. C., Mogensen T. H., Marr N., Spaan A. N., Boisson B., Boisson-Dupuis S., Bustamante J., Puel A., Ciancanelli M., Meyts I., Maniatis T., Soumelis V., Amara A., Nussenzweig M., García-Sastre A., Krammer F., Pujol A., Duffy D., Lifton R., Zhang S.-Y., Gorochov G., Béziat V., Jouanguy E., Sancho-Shimizu V., Rice C. M., Abel L., Notarangelo L. D., Cobat A., Su H. C., Casanova J.-L., Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, eabd4570 (2020). 10.1126/science.abd4570
- Pozzetto B., Mogensen K. E., Tovey M. G., Gresser I., Characteristics of autoantibodies to human interferon in a patient with varicella-zoster disease. J. Infect. Dis. 150, 707–713 (1984). 10.1093/infdis/150.5.707
- Casanova J.-L., Ion Gresser. J. Interferon Cytokine Res. 39, 317–320 (2019). 10.1089/jir.2018.29015.mem
- Walter J. E., Rosen L. B., Csomos K., Rosenberg J. M., Mathew D., Keszei M., Ujhazi B., Chen K., Lee Y. N., Tirosh I., Dobbs K., Al-Herz W., Cowan M. J., Puck J., Bleesing J. J., Grimley M. S., Malech H., De Ravin S. S., Gennery A. R., Abraham R. S., Joshi A. Y., Boyce T. G., Butte M. J., Nadeau K. C., Balboni I., Sullivan K. E., Akhter J., Adeli M., El-Feky R. A., El-Ghoneimy D. H., Dbaibo G., Wakim R., Azzari C., Palma P., Cancrini C., Capuder K., Condino-Neto A., Costa-Carvalho B. T., Oliveira J. B., Roifman C., Buchbinder D., Kumanovics A., Franco J. L., Niehues T., Schuetz C., Kuijpers T., Yee C., Chou J., Masaad M. J., Geha R., Uzel G., Gelman R., Holland S. M., Recher M., Utz P. J., Browne S. K., Notarangelo L. D., Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J. Clin. Invest. 125, 4135–4148 (2015). 10.1172/JCI80477
- Beccuti G., Ghizzoni L., Cambria V., Codullo V., Sacchi P., Lovati E., Mongodi S., Iotti G. A., Mojoli F., A COVID-19 pneumonia case report of autoimmune polyendocrine syndrome type 1 in Lombardy, Italy: Letter to the editor. J. Endocrinol. Invest. 43, 1175–1177 (2020). 10.1007/s40618-020-01323-4
- Casanova J.-L., Su H. C., COVID Human Genetic Effort , A Global Effort to Define the Human Genetics of Protective Immunity to SARS-CoV-2 Infection. Cell 181, 1194–1199 (2020). 10.1016/j.cell.2020.05.016
- Manry J., Laval G., Patin E., Fornarino S., Itan Y., Fumagalli M., Sironi M., Tichit M., Bouchier C., Casanova J.-L., Barreiro L. B., Quintana-Murci L., Evolutionary genetic dissection of human interferons. J. Exp. Med. 208, 2747–2759 (2011). 10.1084/jem.20111680
- Trouillet-Assant S., Viel S., Gaymard A., Pons S., Richard J.-C., Perret M., Villard M., Brengel-Pesce K., Lina B., Mezidi M., Bitker L., Belot A., COVID HCL Study group , Type I IFN immunoprofiling in COVID-19 patients. J. Allergy Clin. Immunol. 146, 206–208.e2 (2020). 10.1016/j.jaci.2020.04.029
- Hadjadj J., Yatim N., Barnabei L., Corneau A., Boussier J., Smith N., Péré H., Charbit B., Bondet V., Chenevier-Gobeaux C., Breillat P., Carlier N., Gauzit R., Morbieu C., Pène F., Marin N., Roche N., Szwebel T.-A., Merkling S. H., Treluyer J.-M., Veyer D., Mouthon L., Blanc C., Tharaux P.-L., Rozenberg F., Fischer A., Duffy D., Rieux-Laucat F., Kernéis S., Terrier B., Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718–724 (2020). 10.1126/science.abc6027
- Harris A., Collins J., Vetrie D., Cole C., Bobrow M., X inactivation as a mechanism of selection against lethal alleles: Further investigation of incontinentia pigmenti and X linked lymphoproliferative disease. J. Med. Genet. 29, 608–614 (1992). 10.1136/jmg.29.9.608
- Blanco-Melo D., Nilsson-Payant B. E., Liu W.-C., Uhl S., Hoagland D., Møller R., Jordan T. X., Oishi K., Panis M., Sachs D., Wang T. T., Schwartz R. E., Lim J. K., Albrecht R. A., tenOever B. R., Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 181, 1036–1045.e9 (2020). 10.1016/j.cell.2020.04.026
- Klein S. L., Pekosz A., Park H.-S., Ursin R. L., Shapiro J. R., Benner S. E., Littlefield K., Kumar S., Naik H. M., Betenbaugh M., Shrestha R., Wu A. A., Hughes R. M., Burgess I., Caturegli P., Laeyendecker O., Quinn T. C., Sullivan D. J., Shoham S., Redd A. D., Bloch E. M., Casadevall A., Tobian A. A. R., Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J. Clin. Invest. 142004 (2020). 10.1172/JCI142004
- Wang T. T., Ravetch J. V., Functional diversification of IgGs through Fc glycosylation. J. Clin. Invest. 129, 3492–3498 (2019). 10.1172/JCI130029
- Burbelo P. D., Riedo F. X., Morishima C., Rawlings S., Smith D., Das S., Strich J. R., Chertow D. S., Davey R. T. Jr.., Cohen J. I., Sensitivity in Detection of Antibodies to Nucleocapsid and Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Coronavirus Disease 2019. J. Infect. Dis. 222, 206–213 (2020). 10.1093/infdis/jiaa273
- Meyer S., Woodward M., Hertel C., Vlaicu P., Haque Y., Kärner J., Macagno A., Onuoha S. C., Fishman D., Peterson H., Metsküla K., Uibo R., Jäntti K., Hokynar K., Wolff A. S. B., APECED patient collaborative, Krohn K., Ranki A., Peterson P., Kisand K., Hayday A., AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies. Cell 166, 582–595 (2016). 10.1016/j.cell.2016.06.024
- Katoh K., Rozewicki J., Yamada K. D., MAFFT online service: Multiple sequence alignment, interactive sequence choice and visualization. Brief. Bioinform. 20, 1160–1166 (2019). 10.1093/bib/bbx108
- Katoh K., Kuma K., Toh H., Miyata T., MAFFT version 5: Improvement in accuracy of multiple sequence alignment. Nucleic Acids Res. 33, 511–518 (2005). 10.1093/nar/gki198
- Saitou N., Nei M., The neighbor-joining method: A new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987). 10.1093/oxfordjournals.molbev.a040454
- Jones D. T., Taylor W. R., Thornton J. M., The rapid generation of mutation data matrices from protein sequences. Comput. Appl. Biosci. 8, 275–282 (1992). 10.1093/bioinformatics/8.3.275
- Woelk C. H., Frost S. D. W., Richman D. D., Higley P. E., Kosakovsky Pond S. L., Evolution of the interferon alpha gene family in eutherian mammals. Gene 397, 38–50 (2007). 10.1016/j.gene.2007.03.018
- Han M. V., Zmasek C. M., phyloXML: XML for evolutionary biology and comparative genomics. BMC Bioinformatics 10, 356 (2009). 10.1186/1471-2105-10-356
- Pestka S., Krause C. D., Walter M. R., Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202, 8–32 (2004). 10.1111/j.0105-2896.2004.00204.x
- Rissin D. M., Kan C. W., Campbell T. G., Howes S. C., Fournier D. R., Song L., Piech T., Patel P. P., Chang L., Rivnak A. J., Ferrell E. P., Randall J. D., Provuncher G. K., Walt D. R., Duffy D. C., Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat. Biotechnol. 28, 595–599 (2010). 10.1038/nbt.1641
- Mathian A., Mouries-Martin S., Dorgham K., Devilliers H., Barnabei L., Ben Salah E., Cohen-Aubart F., Garrido Castillo L., Haroche J., Hie M., Pineton de Chambrun M., Miyara M., Sterlin D., Pha M., Lê Thi Huong D., Rieux-Laucat F., Rozenberg F., Gorochov G., Amoura Z., Monitoring Disease Activity in Systemic Lupus Erythematosus With Single-Molecule Array Digital Enzyme-Linked Immunosorbent Assay Quantification of Serum Interferon-α. Arthritis Rheumatol. 71, 756–765 (2019). 10.1002/art.40792
- Lebon P., Ponsot G., Aicardi J., Goutières F., Arthuis M., Early intrathecal synthesis of interferon in herpes encephalitis. Biomedicine 31, 267–271 (1979).
- Robbiani D. F., Gaebler C., Muecksch F., Lorenzi J. C. C., Wang Z., Cho A., Agudelo M., Barnes C. O., Gazumyan A., Finkin S., Hägglöf T., Oliveira T. Y., Viant C., Hurley A., Hoffmann H.-H., Millard K. G., Kost R. G., Cipolla M., Gordon K., Bianchini F., Chen S. T., Ramos V., Patel R., Dizon J., Shimeliovich I., Mendoza P., Hartweger H., Nogueira L., Pack M., Horowitz J., Schmidt F., Weisblum Y., Michailidis E., Ashbrook A. W., Waltari E., Pak J. E., Huey-Tubman K. E., Koranda N., Hoffman P. R., West A. P. Jr.., Rice C. M., Hatziioannou T., Bjorkman P. J., Bieniasz P. D., Caskey M., Nussenzweig M. C., Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020). 10.1038/s41586-020-2456-9
- Kim H., de Jesus A. A., Brooks S. R., Liu Y., Huang Y., VanTries R., Montealegre Sanchez G. A., Rotman Y., Gadina M., Goldbach-Mansky R., Development of a Validated Interferon Score Using NanoString Technology. J. Interferon Cytokine Res. 38, 171–185 (2018). 10.1089/jir.2017.0127
- Ferreira J. P., Girerd N., Bozec E., Mercklé L., Pizard A., Bouali S., Eby E., Leroy C., Machu J.-L., Boivin J.-M., Lamiral Z., Rossignol P., Zannad F., Cohort Profile: Rationale and design of the fourth visit of the STANISLAS cohort: a familial longitudinal population-based cohort from the Nancy region of France. Int. J. Epidemiol. 47, 395–395j (2018). 10.1093/ije/dyx240
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